Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

Ananda Chapagain; Paul W. Caton; Julius  Kieswich; Petros Andrikopoulos; Nanda Nayuni; Jamie Long; Steven Harwood; Scott Webster; Martin Raftery; Christoph Thiemermann; Brian R. Walker; Jonathan Seckl; Roger Corder; Mohammad  Yaqoob

doi:10.1073/pnas.1312436111

Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

Ananda Chapagain, Paul W. Caton, Julius Kieswich, Petros Andrikopoulos, Nanda Nayuni, Jamie Long, Steven Harwood, Scott Webster, Martin Raftery, Christoph Thiemermann, Brian R. Walker, Jonathan Seckl, Roger Corder, Mohammad Yaqoob

Research output: Contribution to journal › Article › peer-review

29 Citations (Scopus)

Abstract

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1−/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

Original language	English
Pages (from-to)	3817-3822
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	10
Early online date	25 Feb 2014
DOIs	https://doi.org/10.1073/pnas.1312436111
Publication status	Published - 11 Mar 2014

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.1312436111

Cite this

Chapagain, A., Caton, P. W., Kieswich, J., Andrikopoulos, P., Nayuni, N., Long, J., Harwood, S., Webster, S., Raftery, M., Thiemermann, C., Walker, B. R., Seckl, J., Corder, R., & Yaqoob, M. (2014). Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia. Proceedings of the National Academy of Sciences of the United States of America, 111(10), 3817-3822. https://doi.org/10.1073/pnas.1312436111

@article{01577ac18d6e40d9a2ab54bcd58a1447,

title = "Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia",

abstract = "Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1−/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD. ",

author = "Ananda Chapagain and Caton, {Paul W.} and Julius Kieswich and Petros Andrikopoulos and Nanda Nayuni and Jamie Long and Steven Harwood and Scott Webster and Martin Raftery and Christoph Thiemermann and Walker, {Brian R.} and Jonathan Seckl and Roger Corder and Mohammad Yaqoob",

year = "2014",

month = mar,

day = "11",

doi = "10.1073/pnas.1312436111",

language = "English",

volume = "111",

pages = "3817--3822",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Acad Sciences",

number = "10",

}

Chapagain, A, Caton, PW, Kieswich, J, Andrikopoulos, P, Nayuni, N, Long, J, Harwood, S, Webster, S, Raftery, M, Thiemermann, C, Walker, BR, Seckl, J, Corder, R & Yaqoob, M 2014, 'Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 10, pp. 3817-3822. https://doi.org/10.1073/pnas.1312436111

TY - JOUR

T1 - Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

AU - Chapagain, Ananda

AU - Caton, Paul W.

AU - Kieswich, Julius

AU - Andrikopoulos, Petros

AU - Nayuni, Nanda

AU - Long, Jamie

AU - Harwood, Steven

AU - Webster, Scott

AU - Raftery, Martin

AU - Thiemermann, Christoph

AU - Walker, Brian R.

AU - Seckl, Jonathan

AU - Corder, Roger

AU - Yaqoob, Mohammad

PY - 2014/3/11

Y1 - 2014/3/11

N2 - Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1−/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

AB - Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1−/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

U2 - 10.1073/pnas.1312436111

DO - 10.1073/pnas.1312436111

M3 - Article

SN - 0027-8424

VL - 111

SP - 3817

EP - 3822

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 10

ER -

Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this